The impact of radiation dose on the efficacy of definitive chemoradiotherapy in patients with locally advanced esophageal carcinoma: a systematic review and meta-analysis

ABSTRACT To investigate the impact of radiation dose on the efficacy of definitive chemoradiotherapy(dCCRT) in patients with locally advanced esophageal carcinoma. PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Wanfang, and Chinese National Knowledge Infrastructure(CNKI) were searched for eligible studies. Studies that compared high-dose radiation(HD-RT) group with low-dose radiation(LD-RT) group using modern radiotherapy techniques for locally advanced esophageal carcinoma patients in dCCRT were identified. The hazard ratios (HR) for overall survival (OS), progression-free survival (PFS), and the odds ratios (OR) for clinical complete response (cCR), local–regional failure (LRF), distant metastasis (DM), and grade≥3 AEs. Meta-analysis was performed when relevant data were available. Eleven studies involving 1943 patients were included for analyses. The results showed that the HD-RT group had better OS (pooled HR 0.78 [0.70, 0.87], p < .00001), PFS (pooled HR 0.72 [0.55, 0.94], p = .01), cCR (OR 1.52 [1.13, 2.05], p = .005), and LRF (OR 0.60 [0.45, 0.80], p = .0004). In addition, there were no significant differences between the two groups in terms of DM (OR 1.43 [1.00, 2.04], p = .05), grade 3–5 radiation pneumonitis (OR 1.38 [0.71, 2.68], p = .35), grade 3–5 radiation esophagitis (OR 1.36 [0.88, 2.10], p = .17), grade 3–5 other esophageal toxicities(stenosis/fistula/hemorrhage) (OR 1.22 [0.75, 2.00], p = .43), and treatment-related death (OR 1.40 [0.73, 2.68], p = .31). High-dose radiotherapy in definitive CCRT for patients with locally advanced esophageal carcinoma is associated with improved PFS, OS, cCR, and LC with no increase of grade≥3AEs. Simultaneously, we await the preliminary and final results of several ongoing dose-escalation randomized trials. Furthermore, future studies should provide personalized radiotherapy doses for these patients.


Introduction
Patients with locally advanced esophageal carcinoma (LAEC) account for approximately 50% of the total, 1 and the majority of them have lost the opportunity for surgery at the time of diagnosis. The currently recommended treatment modality for these unresectable patients is platinum-based definitive concurrent chemoradiotherapy (CCRT) based on the result of the Intergroup Radiation Therapy Oncology Group (RTOG)-8501. 2 The recommended dose by National Comprehensive Cancer Network (NCCN) was 50-50.4 Gy 3 based on the results of Intergroup Radiation Therapy Oncology Group (RTOG)90-12 4 and INT-0123 (also known as RTOG 94-05). 5 Although even with this modality therapy, survival remains disappointing and with 5-year overall survival (OS) rate of approximately 20%, and the most common mode of treatment failure is locoregional recurrence within the gross tumor volume, which was as high as 50%, 6 especially in patients with LAEC. 7,8 Simultaneously, dose escalation has been shown in numerous clinical trials and meta-analyses to improve local control (LC) and OS with no increase in serious side effects, raising the possibility that this factor may be advantageous in CCRT. [9][10][11][12][13] Nevertheless, the ARTDECO study 14 and the study undertaken by Xu et al 15 came to oppose, indicating that dose escalation has no benefit on OS. Hence, the recommended radiation dose remains controversial. However, many studies included patients at all stages, which may have impacted the findings and reduced the effect of current clinical evidence. Hence, we performed this up-to-date meta-analysis to determine whether dose escalation of CCRT could improve the survival of patients with LAEC.

Study election
Inclusion criteria included: 1) Studies on patients with LAEC (AJCC 6 th : stage II-IVA; AJCC 7 th : stage IB-IIIC; AJCC 8 th : stage IB-IVA). 2) Studies comparing the curative efficacy in LAEC patients with HD-RT or LD-RT. 3) OS must be reported. 4)The most recent and informative publication from the same trial. 5)The language limit to English and Chinese.
The following studies were excluded: 1) Studies on patients with distant metastasis or with other cancers.2) Only 2D radiotherapy techniques or Co-60. 3) single-arm trial, letters, review, case report, meta-analysis, or abstract of meeting.

Data extraction
The following information was gathered from all included studies:1) information and characteristics: first name of author, nation, year of publication, study period, sort of research, clinical stage, gender, histology, groups, patient number, location, radiation dose, regimens, radiation technology, quality.2) primary data: HR and 95% CI of OS and PFS; incidence rate for cCR, LRF, and DM, and grade≥3 adverse events(AEs). Engauge Digitizer version 4.1 (available from: http://digitizer.sourceforge.net/) was applied to read the survival rates from Kaplan-Meier curves, and then the spreadsheet attached to Tierney's paper was used to calculate HR.

Quality assessment
The quality of all included studies was rated separately by two evaluators. The 9-star Newcastle-Ottawa Scale (Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford. htm) was used to assess non-RCTs, with high quality scoring 7-9, medium quality scoring 4-6, and low quality scoring 1-3. The 7-point JADAD scale was used to assess RCTs, with high quality scoring 4-7 and poor quality scoring 1-3.

Statistical analysis
This meta-analysis was carried out using the software of the Review Manager (Rev Man) (version 5.3) and STATA v12.0. I 2 was used to assess statistical heterogeneity. If I 2 ≤ 50%, a fixedeffects model was conducted to synthesize HR and OR; otherwise, a random-effects model was used. The tests were considered statistically significant if P < .05. All the P values were twosided. Begg's and Egger's tests were used to examine the publication bias of PFS and OS. Sensitivity analysis was used to determine the effect of any individual study on the final results.

Results
Eleven studies met the criteria and were incorporated into the meta-analysis ( Figure 1 outlines the selection process flow). The eleven studies consisted of four randomized controlled trials (RCTs), three population-based propensity-scorematched analyses, and four retrospective studies. There was a total of 1943 LAEC patients, of whom 962 received LD-RT while 981 received HD-RT. The detailed information of all studies is reported in Table 1. [14][15][16][17][18][19][20][21][22][23][24] All articles reported overall survival in groups. Patients in the HD-RT group had significant survival benefits compared to patients in the LD-RT group (pooled HR 0.78 [0.70, 0.87], p < .00001, Figure 2a). A fixed model was employed because I 2 < 50% (I 2 = 45%).
Five articles analyzed the DM rates of the two groups. There was no difference between the two groups in this respect (OR 1.43 [1.00, 2.04]; P = .05, Figure 3c). A fixed model was employed because I 2 < 50%.
Eight articles reported grade ≥ 3AEs (Table 2). No significant difference was demonstrated between the two arms in terms of  Figure 4d). A fixed model was employed because I 2 < 50%.

Sensitivity analysis
Sensitivity analysis revealed that the new HRs for OS ( Figure 5a) and PFS ( Figure 5b) were identical to the original HRs, demonstrating that no single study may have significantly influenced the meta-analysis results.

Publication bias
No significant publication bias was found between HD-RT group and LD-RT group among all studies on OS (Figure 5c

Discussion
Does dose escalation of CCRT improve the survival of patients with LAEC? In our study, we focus on patients with locally advanced esophageal carcinoma and summarize the current clinical evidence of dose escalation. The findings demonstrated a higher dose utilizing modern radiation techniques for definitive CCRT of LAEC might reduce LRF and improve PFS, OS, and cCR of patients without increasing toxicity rates compared to low-dose radiotherapy. There have been numerous studies on esophageal cancer dose escalation, but no conclusion has been reached. Based on the findings of the INT0123 study, 5 the dose recommendation for definitive radiotherapy is 50-50.4 Gy. Minsky et al compared the high radiation dose group (64.8 Gy) to the low-dose group (50.4 Gy) with conventional radiotherapy techniques(2D-RT), and no benefit in local control rate or survival rate was observed, but treatmentrelated mortality increased. It was worth noting that the enrolled population contains a higher proportion of patients in the early stages (I-IIB). Moreover, only the primary tumor was treated up to 64.8 Gy, with no dose escalation for involved nodes. Furthermore, HD group radiotherapy treated patients with squamous cell carcinoma (85.8%) and adenocarcinoma (14.2%). In addition, the radiation dose did not meet 50.4 Gy in 7 of the 11 treatment-related deaths in the high-dose group. As a result, the study spurred controversy in its aftermath. Similar results were in other studies even with modern radiotherapy techniques(3D-RT). 25 there were no survival differences between the two groups. Unfortunately, the same outcome was achieved when propensity-score-matched comparisons were attempted to investigate the effect of dose escalation on OS stratified by histologic type and IMRT use.This was a retrospective database-based study, and conclusions were limited by lacking radiotherapy technique and planning, staging and chemotherapy regimens, and salvage regimens for recurrence and metastasis. In another study, 26 twelve patients were assigned to receive a radiation dose of 61.2 Gy and 30 patients to receive 50.4 Gy; dose-related toxicities were encountered in two out of twelve patients in the high-dose group, including grade 3 esophagaomediastinal fistula and grade 4 pericardial effusion. However, it might be limited by the unbalanced sample size and the increased toxicity of chemoradiation therapy, which combines three cytotoxic agents.
However, several studies showed that higher radiation doses resulted in effective local control of locally advanced esophageal cancer. Suh et al 17 suggested that dose escalation in stage II-III locally advanced esophageal carcinoma improved the 2-year local control rate (69% versus 32%, P < .01) and PFS (47% versus 20%, P = .01), with no increase in treatment-related toxicity. Squamous cell carcinoma and adenocarcinoma were among the patients. Finally, high-dose radiotherapy of 60 Gy or more combined with concurrent chemotherapy is an effective therapeutic option for Stage II-III esophageal cancer. In another study, 16 44 patients with   19 retrospectively analyzed the clinical data of 236 patients with stage II-III esophageal cancer and compared 120 patients with radiotherapy doses <60 Gy to 116 patients with ≥60 Gy. The results showed that there was a significant local control advantage (69.1% versus 50.3%, P = .002) and survival advantage (35.1 months versus 22.3 months, P = .043) in high doses and the incidence of treatmentrelated adverse reactions was similar. In another study, 21 higher doses than that used for standard radiotherapy resulted in higher 5-year OS rates (42.8% versus 21%). Similar findings were in other studies. [22][23][24] According to the mentioned research, the benefit of OS and LC in the HD-RT group may base on the biological behavior of solid tumors and squamous cell carcinomas 28,29 and attributed to advancements in radiotherapy technology and imaging technology, which allow for more precise target delineation.And the selection bias of retrospective studies cannot be ignored.
Undoubtedly, the findings of three recent randomized controlled trials must be discussed. This study included the ARTDECO study 14 and the study conducted by Xu et al, 15 whereas the CONCORDE study 30 only reported the results of conference abstracts, which could not be included in this study. According to the ARTDECO study, there was no significant difference in PFS, OS, and Locoregional progression-free survival (LRPFS) between the HD-RT (61.6 Gy) group and LD-RT (50.4 Gy) group. The results may be related to the fact that dose escalation was only delivered to the primary tumor, and 39% of adenocarcinoma patients show different risk factors and biological characteristics from squamous carcinoma. In addition, an excess of fatal bleeding in grade 4 and 5 toxicities in the HD arm occurred. Similarly, Xu et al found no difference toward 3y-OS or PFS or LRPFS between the HD-RT (60 Gy) and LD-RT (50 Gy) groups, but grade 3    Given the contradictory findings of the above studies, we conducted this meta-analysis and indicated that higher doses can benefit patients with LAEC in survival.Inevitably, there are some limitations in this study. At first, the quality of the included studies varied, with four retrospective studies. Second, a small patient population enrolled in some studies, including two RCTs. The studies conducted by Zhu et al and Nayan et al found no lung or esophageal side effects (grade≥3), which could be attributed to the small sample size and individual differences in radiation sensitivity. Another reason that Zhu et al. chose patients with neck and upper thoracic esophageal cancer was doubtless. Third, the stages of patients were based on different versions instead of individual patient data. Finally, some studies lacked critical information such as radiation field, dosage distribution, and chemotherapy regimens. These limitations may have an impact on the actual value of our research. More RCTs are needed to back up our findings.

Conclusion
High-dose radiotherapy in definitive CCRT for patients with locally advanced esophageal carcinoma is associated with improved PFS, OS, cCR, and LC with no increase of grade≥3AEs. Simultaneously, we await the preliminary and final results of several ongoing dose-escalation randomized trials. Furthermore, future studies should provide personalized radiotherapy doses for these patients.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article.

Data availability statement
All data, models, and code generated or used during the study appear in the submitted article.